Polycystic ovary syndrome (PCOS) affects 5-10% of women of reproductive age, is the most common endocrine abnormality, and increases risk for cardiovascular disease during the reproductive years as well as after menopause. The main symptom of PCOS is hyperandrogenemia, but is also characterized by hypertension, ovarian dysfunction, metabolic abnormalities, and chronic inflammation. Mechanisms responsible for elevated BP in women with PCOS are unclear. Using a hyperandrogenemic female (HAF) rat model, we have mimicked many of the characteristics of hyperandrogenemia in women: elevated BP, ovarian dysfunction, increases in body weight and visceral adiposity, increased plasma leptin and TNF-1. These findings are exciting and novel since the effects of androgens on females are unique and different than in males. Blood pressure (BP) in women with PCOS is normalized with renin- angiotensin system (RAS) blockers. In preliminary studies, enalapril decreases BP more in HAF rats than in controls, and angiotensinogen is increased, suggesting that the RAS is upregulated and in part mediates their HT. We have preliminary data that enalapril (ACE inhibitor) reduces BP more in HAF rats than controls. Women with PCOS have activated sympathetic nervous system (SNS). HAF rats have increased plasma leptin, a cytokine released from adipocytes, that contributes to SNS activation and increases BP by stimulating brain pro-opiomelanocortin pathway via melanocortin 4 receptor (MC4R) activation. Preliminary studies with combined 11-, 21/2-adrenoceptor blockade or MC4R blockade with SHU-9119 reduced BP in HAF rats more than in controls, suggesting that activation of the SNS in HAF rats is mediated by MC4R activation. The SNS may contribute to the elevated BP in HAF rats directly or via the RAS since SNS activation can increase renin release. However, preliminary data with blockade of the RAS with losartan plus adrenergic blockade reduced BP further in HAF than adrenergic blockade alone, suggesting that the RAS plays a role in the elevated BP in HAF rats independent of the SNS. TNF-1 also increases in HAF rats, and in preliminary studies, etanercept, the soluble TNF-1 receptor, reduced BP. Enalapril also reduced intrarenal TNF-1 in HAF rats. Based on our exciting preliminary data, the studies proposed in this application will test the novel, integrative hypotheses that DHT in females increases visceral adiposity which results in hyperleptinemia and MC4R activation, leading to SNS activation; that DHT in females activates the RAS by a combination of androgen-mediated increases in renin and angiotensinogen synthesis, and SNS activation and increased renin release. This leads to an increase in Ang II that increases TNF-1 that contributes to the elevated BP in HAF rats. The aims of the proposal are: 1. To test the hypothesis that elevated BP in HAF rats is due in part to activation of the SNS, due to MC4R stimulation; 2. To test the hypothesis that elevated BP in HAF rats is due in part to an activated RAS, caused by increased SNS activity to cause renin release and by DHT-mediated increase in synthesis of RAS components, such as angiotensinogen and renin; 3. To test the hypothesis that elevated BP in HAF rats is due in part to increased TNF1, produced by increased adiposity and/or Ang II. Results from these studies will provide new information that can be used to design new therapeutic options to treat HT in women with hyperandrogenemia, such as in PCOS. PUBLIC HEALTH RELEVANCE: The studies proposed will determine the mechanisms responsible for hypertension in hyperandrogenemic female rats, as a model of hyperandrogenemic women, such as women with polycystic ovary syndrome. The quantitative contributions of the sympathetic nervous system, the renin-angiotensin system, and inflammation to the hypertension in hyperandrogenemic rats will be determined.